Including Information on the Therapeutic Window in Bioequivalence Acceptance
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A novel bioequivalence limit is proposed taking into account the therapeutic window.
The therapeutic range is introduced as the ratios maximum tolerated dose/therapeutic dose (MTD/D) and the therapeutic dose/lowest effective dose. The performance of the new acceptance range was compared with the methods of Schuirmann and Karalis. The method was retrospectively applied to data of three drugs with a narrow therapeutic window (phenytoin, theophylline and digoxin).
Simulations and examples show that the resulting bioequivalence limits are (1) narrow for narrow-index drugs, (2) expanded for highly variable drugs with a wide therapeutic window and (3) similar to the classical limits for less variable drugs with a wide therapeutic range.
The approach has the desirable property of resulting in a more narrow acceptance range for doses near the boundaries of the therapeutic window and a wider acceptance range for products with a broad therapeutic window.
KEY WORDSaverage bioequivalence bioavailability individual bioequivalence therapeutic window
Financial support from the IAP Research Network P6/03 of the Belgian Government (Belgian Science Policy) is gratefully acknowledged.
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